Treatment for intestinal gas, bloating, microscopic colitis, inflammatory bowel disease and traveler&#39;s diarrhea using colloidal bismuth subcitrate

ABSTRACT

A method of treatment for intestinal gas bloating, microscopic colitis, traveler&#39;s diarrhea and inflammatory bowel disease, said method comprising ingesting an effective quantity of a composition comprising colloidal bismuth subcitrate to eliminate gastrointestinal discomfort.

CLAIM FOR PRIORITY/RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 60/869,003 filed Dec. 7, 2006 entitled TREATMENT FOR INTESTINAL GAS,BLOATING, MICROSCOPIC COLITIS, INFLAMMATORY BOWEL DISEASE AND TRAVELERSDIARRHEA USING COLLOIDAL BISMUTH SUBCITRATE, which application is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention is directed to compositions and methods for the treatmentof intestinal gas and other gastrointestinal disorders. Moreparticularly, the invention relates to methods and compositions fortreating intestinal gas, bloating, microscopic colitis, inflammatorybowel disease and traveler's diarrhea using colloidal bismuth subcitrate(CBS).

BACKGROUND OF THE INVENTION

Gas production normally occurs in the human colon, also known as thelarge intestine. Colonic gas production takes place when bacteriaresiding normally in the colon metabolize undigested or partiallydigested substances. This fermentative process results in the formationof hydrogen (H2), methane (CH₄), and CO₂. Incomplete upper intestinaldigestion and absorption of some food-based carbohydrates is a normaloccurrence. Sometimes these substances do not undergo breakdown andabsorption across the mucosa (also called the lining) of the smallintestine. Unabsorbed carbohydrates are passed by normal intestinalmuscular contraction towards the colon. Ultimately, these substancesenter the colon in their original form.

Bacterial metabolism of these unabsorbed carbohydrates and some aminoacids results in gas production within the colon. Undigestedpolysaccharides from fruits and vegetables are also sources ofintestinal gas formation. Intestinal gas is eliminated from thegastrointestinal tract in several ways. Belching, or forced evacuationof gas from the stomach, is utilized primarily for the removal ofswallowed air and ingested CO₂ from carbonated beverages. Some gasdiffuses from the intestinal lumen into the bloodstream. Ultimately, thelungs excrete these gases. Additionally, specialized colonic bacteriamay utilize gas produced by fermentation by other bacteria as a sourceof fuel. These methods of gas elimination make up only a small portionof the methods of colonic gas removal. The majority of intestinal gas iseliminated by passage out of the colon through the anus as flatus.

In patients with intestinal malabsorption, disaccharidase deficiencies,small intestinal and pancreatic diseases and other more poorlycharacterized conditions, large quantities of disaccharides enter thecolon where they are fermented by colonic bacteria. These individualsare prone to the production of large volumes of intestinal gas.Excessive intestinal gas results in the symptoms of excessive flatus,bloating, diarrhea and abdominal distension. Of interest, passage ofvoluminous or noxious flatus also appears to be a common complaint innormal persons.

Patients with irritable bowel syndrome and other functionalgastrointestinal disorders frequently complain of abdominal bloating,cramping and flatulence. However, clinical studies have generally failedto demonstrate excessive gas production in these individuals. Elderlypatients with decreased digestive function, persons with lactose orfructose intolerance and many other patients commonly complain ofexcessive gas. If diminished anal sphincter function is present, (asoccurs in the elderly as well as persons with prior anal sphincterinjury or surgery), excessive gas production may result in gasincontinence, an embarrassing condition that may result in diminishedquality of life. At present, patients with difficulty with excessive gasproduction, abdominal bloating or control of colonic gas have fewreadily available treatment options.

Simethicone is an over-the-counter product marketed for the relief ofabdominal discomfort secondary to gas buildup. It acts as emulsifyingagent and changes the surface tension of gas bubbles in the stomach andintestines. In theory, simethicone causes small gas bubbles to jointogether into larger bubbles. It is thought that these larger gasbubbles are more easily eliminated from the body by belching or passingflatus. Unfortunately, this proposed mechanism has not been proven to bebeneficial to patients. Additionally, it may be hypothesized that easierpassage of large gas bubbles may result in adverse effects ofsimethicone in patients with excessive intestinal gas production orthose with gas incontinence.

Lactase enzyme supplements such as Lactaid and DairyEase improve dairydigestion in patients with lactose intolerance. Patients that arelactase deficient will incompletely absorb milk products when theyingest dietary substances that contain dairy. These products will reducethe formation of gas in many patients that have the symptoms of lactoseintolerance.

Activated charcoal has been shown to absorb a variety of organic andinorganic compounds. This includes absorption of hydrogen and nitrogengasses, which in theory could reduce the volume of flatus in personscomplaining of excessive gas passage. Additionally, binding of thesulfur containing gasses (hydrogen sulfate and methanethiol) by charcoalcould potentially reduce the unpleasant odor of gasses in thesepatients. Although some clinical trials have demonstrated benefits ofactivated charcoal in reducing gas passage, other studies have failed todemonstrate this positive effect. Activated charcoal ingestion may alsopredispose to vitamin deficiencies and malabsorption of drugs.

Although laboratory studies have demonstrated that bismuth subsalicylatemay decrease overall bacterial production of noxious gases such ashydrogen sulfite, no clinical studies have demonstrated effectiveness ofthis compound for the treatment or prevention of excessive intestinalgas. No formal studies of bismuth citrate have been performed todetermine its efficacy in the treatment of excessive gas or abdominalbloating.

Microscopic colitis is a form of chronic diarrheal illness that appearsto be increasing in prevalence in the United States. This condition,which is characterized by the daily occurrence of frequent waterydiarrhea, is most commonly seen in women over the age of fifty.Diagnosis of microscopic colitis is made by the performance ofcolonoscopy with multiple biopsies of the mucosal lining throughout thecolon. Generally, the colonic mucosa is normal by endoscopic appearance.However biopsies reveal chronic inflammation of the colonic mucosa. Twocharacteristic patterns of mucosal inflammation are seen in microscopiccolitis. In collagenous colitis, thickening of the lamina propriacollagen layer is seen in association with infiltration of chronicinflammatory cells. In lymphocytic colitis, marked lamina propriainfiltration of lymphocytes, with associated intra-epitheliallymphocytes are seen. A variety of treatments have been recommended formicroscopic colitis. These include systemic corticosteroids, which mayresolve symptoms without histologic improvement, topical5-aminosalicylic acid containing drugs and a variety of miscellaneoustreatments.

Recently, randomized, controlled trials have shown that the topicalsteroid, enteric-coated budesonide (Entocort) appears to be a highlyeffective treatment for microscopic colitis. An open-label study ofchronic, high dose bismuth subsalicylate (8 chewable Pepto-Bismol dailyfor 8 weeks) resulted in improvement of symptoms in 11 of 12 patientsstudied. Each tablet contains Bismuth subsalicylate 262 mg. In thestudy, nine patients (75%) had complete resolution of colitis onexamination of colonic biopsies. A very small randomized, controlledtrial of bismuth subsalicylate appeared to confirm these initialfindings. By definition, subjects in these studies were excluded if theywere allergic to aspirin. Most clinicians are unable to duplicate thesuccess rates of these studies in treating the symptoms and eradicatingmicroscopic colitis due to patient's inability to tolerate these dosesof bismuth subsalicylate.

Traveler's diarrhea occurs as an acute illness in persons visitingcountries with poor sanitary conditions. The condition develops as aform of food poisoning after consumption of food or water containingpathogenic bacteria, viruses or parasitic organisms. The majority ofcases of traveler's diarrhea are due to the E. coli bacteria strainsthat secrete enterotoxins.

Bismuth subsalicylate is commonly used for the prevention of traveler'sdiarrhea and has been FDA approved for the control of traveler'sdiarrhea. As with other conditions mentioned, a relatively high dose ofbismuth subsalicylate is required for this indication. Currentrecommended doses of bismuth subsalicylate to prevent traveler'sdiarrhea are 2 chewable tablets (each containing Bismuth subsalicylate262 mg), four times daily. A 66% reduction in the occurrence of diarrheais achieved with this dosage. Unfortunately, this dose will not betolerated by a significant number of individuals using bismuthsubsalicylate to prevent traveler's diarrhea, particularly if the commonand unpleasant side effects of these doses of bismuth subsalicylatedevelop during travel.

Bismuth subsalicylate is also a commonly used over-the-counter treatmentfor benign forms of infectious diarrhea in adults and children. It isalso prescribed for upset stomach (dyspepsia).

Antibiotics, particularly metronidazole and ciprofloxacin, are used asadjunctive pharmacotherapy for the treatment of acute episodes andmaintenance therapy for ulcerative colitis and Crohn's disease(collectively known as inflammatory bowel disease, or IBD). Themechanisms by which antibiotics are effective for these conditions arenot known, but alteration of gastrointestinal flora and directanti-inflammatory activity appear to be an important factors. The shortand long term use of antibiotics in these conditions can be problematic.Antibiotics may cause diarrhea, thus worsening these conditions.Additionally, these drugs may wipe out beneficial bacteria and causeovergrowth of resistant organisms. Long term use of metronidazole mayresult in injury to the nerves of the hands and feet. In some patients,this form of nerve injury, termed neuropathy, may be permanent.

SUMMARY OF THE INVENTION

The invention involves the oral administration of colloidal bismuthsubcitrate (CBS), and other forms and alterations of bismuth citrate.Reference to CBS or colloidal bismuth subcitrate should be understood toinclude ranitidine bismuth citrate and other forms and alterations ofbismuth citrate. CBS has many advantages over the currently availablebismuth subsalicylate because of decreased side effects and bettertolerability of the medications at the doses required to treatappropriate conditions. The compounds according to the present inventionmay also be used for individuals that are allergic to aspirin. Thesesubstances may be used for the treatment of excessive gas production.These compounds may also be used for the prevention and treatment oftraveler's diarrhea. These compounds may also be used to reduce thesymptoms of microscopic colitis and to induce remission of thiscondition. Additionally, these compounds may be used for the medicalmanagement of abdominal bloating and diarrhea associated with functionalbowel disorders such as irritable bowel syndrome. These compounds mayalso be used as adjunctive initial or maintenance therapy for IBD.

A therapeutic dosage of CBS or salts of bismuth subcitrate according tothe present invention is a dosage of up to 2700 mg daily. This dosagemay be utilized for up to 8 weeks for the treatment of microscopiccolitis. Doses of ranitidine bismuth citrate would be 800 mg three timesdaily.

Doses of two to eight capsules CBS (up to 2700 mg) daily may beadministered to prevent traveler's diarrhea in persons going to endemicareas. Doses of two to eight CBS capsules daily in divided doses may beutilized for the management of excessive gas production for up to 12weeks duration. Subsequently, up to 2700 mg/day bismuth citrate may beused on an as needed basis for these conditions. Doses of ranitidinebismuth citrate would be up to 800 mg three times daily.

According to one aspect of the present invention treatment forintestinal gas bloating, microscopic colitis and traveler's diarrhea,comprises ingesting an effective quantity of a composition comprisingbismuth citrate (or colloidal bismuth subcitrate) for gastrointestinaldiscomfort. The composition of the aforementioned method may containbetween 125 and 900 mg of bismuth subcitrate. Moreover, the compositionmay be administered once, twice or up to six times daily. The daily doseof ranitidine bismuth citrate would be 400-800 mg daily or up to threetimes per day.

The composition may be administered in a form selected from the groupconsisting of chewing gums, lozenges, troches, and combinations thereof.

DETAILED DESCRIPTION OF THE INVENTION

Bismuth compounds have been used since the 1700s as treatments for avariety of medical conditions. The most common uses ofbismuth-containing compounds are for the treatment of diarrhea anddyspepsia. A variety of bismuth salts have been administered as remediesfor gastrointestinal disorders via the oral route. The only commerciallyavailable form of bismuth in the United States at present is bismuthsubsalicylate (Pepto-Bismol; Procter & Gamble Co., Cincinnati Ohio).

More recently, ranitidine bismuth citrate (Tritec, GlaxoPharmaceuticals) was FDA approved as a component of treatment for theHelicobacter pylori infection. Tritec was marketed as a portion oftriple antibiotic therapy for Helicobacter pylori infection. Theadvantage of adding a bismuth-containing compound to antibiotic therapyfor Helicobacter pylori infection is that bismuth limits the productionof antibiotic-resistant organisms. This is particularly important inEuropean countries, where strains of Helicobacter pylori that areresistant to erythromycin and metronidazole had been identified. Despiteits ease-of-use, very low side effect profile, and potential advantagein prevention of antibiotic-resistant Helicobacter pylori organisms, theuse of Tritec never became popular in the United States and is no longercommercially manufactured or available in this country.

Bismuth subsalicylate is a commonly used over-the-counter form ofbismuth used for the treatment for non-specific gastrointestinalsymptoms and diarrhea. A single clinical trial has been publishedsuggesting that bismuth subsalicylate, administered as 8 chewable 262 mgtablets daily for eight weeks resulted in the diminution of the symptomsof collagenous colitis. The complete resolution of diarrhea and colitisoccurred in nine of twelve patients that completed that open-labelclinical trial.

A randomized, placebo-controlled trial of bismuth subsalicylate, three262 mg tablets orally three times a day for eight weeks was performed innine patients. Four of nine patients received bismuth subsalicylate andall of these demonstrated clinical and histologic improvement, incontrast to no effect seen in the placebo group. Unfortunately, thisstudy was never published in a peer-reviewed journal and only appearedabstract form.

The FDA has approved the use for bismuth subsalicylate for theprevention and treatment of traveler's diarrhea an acute diarrheaillness often produced by infection with a strain of E. coli thatsecretes enterotoxic chemical compounds. Bismuth subsalicylateadministered in the doses used in the studies (8-9 262 mg chewablecapsules three times/day) for the treatment of microscopic colitis andfor the prevention of traveler's diarrhea. At these doses, bismuthsubsalicylate has the significant disadvantage of producing a number ofside effects. These side effects include a metallic taste in the mouth,ringing in the ears (tinnitus) and other effects of the salicylateportion of the drug. Nonetheless, in the clinical trials of bismuthsubsalicylate for microscopic colitis, no patient reportedly developedtoxic side effects of bismuth subsalicylate and measured serum bismuthlevels remained well within the safe range in all study patients.Clinical experience with these doses of bismuth subsalicylate for thetreatment of microscopic colitis has generally not been as successful asthe published trials. Most patients are unable to complete an 8 to 12week course of treatment due to the large number of side effects withthese doses of bismuth subsalicylate.

Colloidal bismuth subcitrate (CBS) has never been utilized as astand-alone treatment for gastric and duodenal ulcers, Helicobacterpylori infection and nonulcer dyspepsia.

Applicant has discovered that Bismuth citrate offers many advantagesover bismuth subsalicylate and may be useful for the treatment of avariety of conditions. Since bismuth citrate does not containsalicylates, potential side effects from the use of salicylatesincluding gastrointestinal mucosal inflammation, salicism (tinnitus,dizziness and possibly kidney damage), taste disturbances and othercentral nervous system (CNS) side effects would not be expected tooccur. Allergic reactions would be exceptionally rare and patients thatare allergic to aspirin could take the drug.

The consistent safety of this compound was emphasized in a review of 20clinical studies of ranitidine bismuth citrate including a total of morethan 5000 patients performed by Pipkin, et al. They found that the sideeffects of ranitidine bismuth citrate were no different than those seenwith ranitidine alone. The authors concluded that like ranitidine alone,the combination drug ranitidine bismuth citrate had a well-documentedsafety profile for clinical use. Like bismuth subsalicylate, colloidalbismuth subcitrate (CBS) is a poorly absorbed substance that achievesvery low peak levels when orally administered over a prolonged durationat therapeutic doses. CBS works at the gastrointestinal mucosal levelwhere it has both an antibacterial effect and mucosal protective effect.In addition, CBS binds bile salts and to epithelial growth factor.Unlike bismuth subsalicylate, CBS increases endogenous prostaglandin andalkali secretion. This results in improved gastrointestinal blood flowand enhancement of gastrointestinal mucosal protection. A number ofstudies have demonstrated that safe serum bismuth levels occur whenthese levels are measured after the ingestion of up to 480 mg per day ofCBS for more than 4 weeks.

Other studies demonstrated the safe use of 480 mg of CBS daily for 8weeks for nonulcer dyspepsia. The only episodes of acute reversiblerenal failure demonstrated after the ingestion of bismuth subcitratewere seen in with an overdose of the drug. Chronic encephalopathy, acentral nervous system disease seen with other forms of bismuth saltshas been occasionally described in patients consuming bismuthsubsalicylate. It is only been reported once in a patient with renalimpairment consuming prolonged high doses of bismuth subcitrate. In factin a review of the pharmacology of bismuth containing compounds,published in the journal Reviews of Infectious Diseases, Lambert hasstated that bismuth compounds “administered for short duration tosubjects with normal renal and hepatic function are rarely toxic.Toxicity has mainly resulted from unsupervised and indiscriminate use ofthese compounds”. Lambert also stated that both the clinical effects andpharmacokinetics of CBS has been carefully analyzed scientifically.

The inventor has specific clinical experience with the use of CBS. Sixpatients who had episodic both severe flatus passage andgastrointestinal discomfort after the consumption of large quantities ofnonabsorbable carbohydrates were treated with CBS obtained from acompounding pharmacy. In all six patients, CBS 125 mg, 1 or 2 capsulesper day or twice a day for one to two days completely eliminated all ofacute symptoms of excess of gas passage. No toxic effects were noted inthese individuals. A single dose of CBS 125 mg was administered to a dogwith excessive and bothersome gas following a large meal including tablefood. Complete session of flatus occurred following administration ofthis single dose. One patient with symptomatic microscopic colitis hadcomplete resolution of symptoms after one month of CBS 600 mg threetimes daily.

Because of the well-established safety of CBS, its positive effect ongastrointestinal function, poor absorption and limited risk for toxicityand allergic reactions, CBS is an ideal compound for the treatment of avariety of gastrointestinal disorders. It appears to be effective forthe treatment of excessive gas at low doses that would not be expectedto result in toxicity, even when administered on a chronic basis. It isproposed that this substance can be utilized for the treatment of excessof gas production, gastrointestinal bloating, and irritable bowelsyndrome with excessive of diarrhea, and microscopic colitis includingcollagenous colitis and lymphocytic colitis. It may also be useful asreplacement for conventional antibiotic therapy for IBD.

It may also be used for dyspepsia or the aforementioned indications inpatients that are allergic to aspirin. All of these treatments would beadministered daily for limited time (8 weeks or less) with subsequent onan as needed basis.

According to another aspect of the invention, CBS may be administered incombination with one or more additional compositions or products such assimethicone at a dosage such as 50-200 mg/capsule, up to 1000 mg/day.The simethicone may be replaced with activated charcoal at a dosage of100-500 mg/capsule, up to 3000 mg/day.

CBS may further be administered in combination with a steroid or otheranti-inflammatory such as budesonide 1-3 mg per capsule, up to 9 mg/day;anti-inflammatory mesalamine (5 ASA) 100-500 mg/capsule, up to 2500mg/day; or a steroid, anti-inflammatory or antibiotic such as Rifaximinfor inflammatory bowel disease. For example, combination of CBS 125-600mg and 5-ASA 400-800 mg in a delayed release capsule such as Eudragit-Swould be suitable for treating microscopic colitis. Dosage range wouldbe 3-12 capsules per day.

Alternatively, 5-ASA could be complexed to CBS as a compound or mixturefor the same purpose. This treatment could also be used for ulcerativecolitis or Crohn's disease. This complex could also be delivered as astandard or delayed-release tablet or standard or delayed releasecapsule.

Combination or CBS with a steroid could include CBS 125-600 mg plusbudesonide 1-3 mg or predisone 1-20 mg. These may be in a standardtablet or capsule, or delayed release tablet or capsule. Combinationtherapy with an antibiotic could include a combination of CBS 125-600 mgwith ciprofloxacin. In addition, these doses of CBS may be combined withRifaximin 100 or 200 mg in standard or delayed release capsules oramoxicillen 250-500 mg in standard or delayed-release capsules.

For treatment of intractable gas, CBS 125-600 mg may be combined withsimethicone 10 to 750 mg, peppermint oil 100-1000 mg, chamomile 10-1000mg activated charcoal 10-1000 mg, ginger 10-1000 mg, and/or chlorophyll10-1000 mg. Essential oils of these herbal preparations may be used aswell. For the treatment of irritable bowel syndrome, CBS may be combinedwith hyocyamine 0.125-0.375 mg or dicyclomine 5-20 mg, chlorodiazepoxide1-10 mg and clinidium 1-10 mg or any of the above combinations.

Colloidal bismuth citrate, alone or in combination with otheringredients, may also be administered in enema or suppository form. Inaddition, an ointment or paste containing these compounds may beutilized.

According to another aspect of the invention, CBS may be used to treatmicroscopic colitis by administering CBS in combination with one or moreof 5-ASA (mesalamine), budesonide, azathioprine, or bromolaine.

According to another aspect of the invention, CBS may be used to treattraveler's diarrhea by administering CBS in combination with one or moreof ciprofloxacin, amoxicillen (with or without clavulonate),trimethoprim/sulfamethoxazole, levaquin, Rifaximin, or metronidazole.

According to another aspect of the invention, CBS may be used to treatintractable gas and/or bloating by administering CBS in combination withone or more of simethicone, charcoal, chlorophyll, peppermint oil,chamomile, hyocyamine, or ginger.

According to another aspect of the invention, CBS may be used to treatdyspepsia by administering CBS in combination with one or more of PPI,sucralfate, guar gum, ginger, or chlorophyll.

It should be noted that each of the drug combinations disclosed hereinmay be mixtures, compounds or salts. Moreover, the CBS alone or incombination with one of the additional ingredients disclosed above maybe administered using capsules or tablets, pH sensitive capsules (suchas Eudragit L, S or N), or other delayed release tablets or capsules.

The foregoing description of the invention is illustrative only, and isnot intended to limit the scope of the invention to the precise termsset forth. Further, although the invention has been described in detailwith reference to certain illustrative embodiments, variations andmodifications exist within the scope and spirit of the invention asdescribed and defined in the following claims.

I claim:
 1. A method of treatment for intestinal gas bloating,microscopic colitis and traveler's diarrhea, said method comprisingingesting an effective quantity of a composition comprising colloidalbismuth subcitrate to eliminate gastrointestinal discomfort.
 2. Themethod according to claim 1, wherein the composition contains at least125 mg of colloidal bismuth subcitrate.
 3. The method according to claim2, wherein the composition is administered once daily.
 4. The methodaccording to claim 2, wherein the composition is administered twicedaily.
 5. The method according to claim 2, wherein the composition isadministered up to six times a day.
 6. The method according to claim 1,wherein the composition contains between 125 mg and 900 mg of colloidalbismuth subcitrate.
 7. A topical oral dosage selected from the groupconsisting of chewing gums, lozenges, troches, and combinations thereof,wherein the topical oral dosage form comprises a pharmaceutically activeagent effective against intestinal gas bloating, microscopic colitis andtraveler's diarrhea, wherein the pharmaceutically active agent comprisescolloidal bismuth subcitrate.
 8. The topical oral dosage of claim 7wherein the dosage form is a chewing gum.
 9. The topical oral dosage ofclaim 7 wherein the dosage form is a lozenge.
 10. The topical oraldosage of claim 7 wherein the dosage form is a troche.
 11. The topicaldosage of claim 7 wherein the topical dosage form is chewing gum. 12.The topical dosage of claim 11 wherein the chewing gum comprises betweenabout 125 mg and about 900 mg of colloidal bismuth subcitrate.
 13. Themethod according to claim 1, wherein the composition contains ranitidinebismuth citrate at a dose of 400 mg, administered daily or up to threetimes per day.
 14. The method according to claim 1, wherein thecomposition contains ranitidine bismuth citrate at a dose of 800 mg,administered daily or up to three times per day.
 15. The methodaccording to claim 1, wherein the composition further contains one ormore of the following simethicone, a steroid, an anti-inflammatory, andan antibiotic.